Chronic itch is a presenting sign in numerous diseases associated with the skin, immune and nervous systems. Chronic itch is largely resistant to conventional antihistamines, and few effective therapies are available. In order to develop novel therapeutics against chronic itch, there is a pressing need for identification of signaling mechanisms by which chronic itch is inhibited. We have shown that gastrin-releasing peptide receptor (GRPR) is an important receptor for the development of chronic itch. More recently, we found that PKA activation attenuates itch by inhibiting GRPR function. Aim 1 is to determine whether PKA activation inhibits itch by blockade of GRPR function. Aim 2 is to examine the role of PKA in GRPR phosphorylation. The proposed studies are highly translational because it will provide mechanistic insights into PKA-mediated inhibition of itch transmission and may expand the pool of the targets that might be explored for designing novel PKA activation-based anti-pruritus therapies.